Hypertension is more prevalent in blacks than in Caucasians and is disproportionately severe, leading to a higher rate of clinical complications. The overall hypothesis is that the increased tissue AngII activity in blacks, usually attributed to "race" itself, is actually determined by identifiable genetic factors. Candidate genes within the RAAS include angiotensinogen, the AT1 receptor, aldosterone syntheses, 11-OH-steroid dehyodrogenase and angiotensin-converting enzyme. The phenotypes of increased AngII activity may be compounded by decreased activity of vasodilator pathways (preliminary data highlight racial differences in the kallikreinkinin system), adding kallilrein and endothelial nitric oxide syntheses (eNOS) to the list of candidate genes. They plan to use physiologic and pharmacologic tools to support this hypothesis, devoting special recruitment methods to enroll large numbers of black subjects. Especially among blacks, the interacting contribution of environmental factors to the development and maintenance of hypertension cannot be ignored. We plan to explore three factors that may interact with genetic predisposition to hypertension. The first is obesity, already shown to predict abnormal renal responses to AngII, with its effect dependent upon angiotensinogen genotype. The most likely elemental candidate interacting with genotype is dietary potassium; urinary potassium has often measured lower among blacks, and potassium is likewise intimately involved in control of the tissue kallikrein-kinin system. Finally, our preliminary evidence suggests that a salient feature describing blunted AngII adrenal responsiveness among Caucasians - a sexual dimorphism - is absent among blacks. Young black women in particular lack the protection seen in young white women, which may underlie the higher cardiovascular morality rates seen in black women. They hypothesize that genetic differences in blacks modulate estrogen's effect on the RAAS, perhaps by interfering with its binding to estrogen response elements and therefore gene transcription.